Filap

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FILUP (FILUP)

Composition:

Active substance: sildenafilum;

One film-coated tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;

Excipients: microcrystalline cellulose; anhydrous calcium hydrogen phosphate; sodium croscarmellose; magnesium stearate; film coating: Opadry Red 06B 55000: (hypromellose, Ponceau 4R (E 124), polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172), indigo carmine (E 132)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: red film-coated triangular tablets with rounded edges, embossed with «S22» on one side and smooth on the other;

100 mg tablets: red film-coated triangular tablets with rounded edges, embossed with «S23» on one side and smooth on the other.

Pharmacotherapeutic group. Agents used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological properties.

Pharmacodynamics.

Sildenafil is an oral medicinal product for the treatment of erectile dysfunction. In the presence of sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, increasing the levels of cyclic guanosine monophosphate (cGMP), resulting in relaxation of the smooth muscle in the corpus cavernosum and allowing blood inflow.

Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), which is cGMP-specific and located in the corpus cavernosum, where PDE5 is responsible for cGMP breakdown. Sildenafil affects erection through peripheral mechanisms of action. Sildenafil does not exert a direct relaxant effect on isolated human corpus cavernosum, but it potently enhances the relaxant effect of NO on this tissue. When sexual stimulation occurs along the activated NO/cGMP metabolic pathway, inhibition of PDE5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Thus, sexual stimulation is necessary to achieve the expected positive pharmacological effect of sildenafil.

Effect on pharmacodynamics

In vitro studies have shown that sildenafil is selective for PDE5, which is involved in the erectile process. It has a more potent effect on PDE5 than on other known phosphodiesterases. Its selectivity is 10-fold higher for PDE5 than for PDE6, which is involved in the phototransduction pathway in the retina. At the maximum recommended dose, sildenafil's selectivity is 80-fold higher than for PDE1, and more than 700-fold higher than for PDE2, 3, 4, 7, 8, 9, 10, and 11. Specifically, sildenafil is more than 4000-fold more selective for PDE5 than for PDE3, the cAMP-specific phosphodiesterase isoenzyme involved in regulating cardiac muscle contractility.

Pharmacokinetics.

Absorption

Sildenafil is rapidly absorbed. Maximum observed plasma concentration is reached within 30 to 120 minutes (median 60 minutes) after oral administration under fasting conditions. The mean absolute oral bioavailability is 41% (range 25–63%). After oral administration, AUC and Cmax of sildenafil increase proportionally with dose within the recommended dosage range (25–100 mg).

When sildenafil is taken with food, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

Distribution

The mean volume of distribution at steady state (Vd) for sildenafil is 105 L, indicating tissue penetration. The mean peak total plasma concentration of sildenafil after a single 100 mg oral dose is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in a mean peak free plasma concentration of sildenafil of 18 ng/mL (38 nmol). Protein binding is independent of the total drug concentration.

In healthy volunteers who received sildenafil (single 100 mg dose), less than 0.0002% (mean 188 ng) of the administered dose was detected in semen 90 minutes after administration.

Metabolism and elimination

Sildenafil clearance is primarily mediated by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and exhibits approximately 50% of the in vitro activity of the parent compound against PDE5. Plasma concentrations of this metabolite are approximately 40% of those observed for sildenafil.

The N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 hours.

Total clearance of sildenafil is 41 L/h, and the terminal half-life is 3–5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites predominantly in feces (approximately 80% of the administered dose) and to a lesser extent in urine (approximately 13% of the administered dose).

Pharmacokinetics in special patient populations.

Elderly patients.

In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in plasma concentrations of sildenafil and the active N-desmethyl metabolite approximately 90% higher than those observed in younger healthy volunteers (aged 18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal impairment.

In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil were not altered after a 50 mg oral dose. Mean AUC and Cmax values of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched healthy volunteers without renal impairment. However, due to substantial inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88%, respectively, compared to age-matched healthy volunteers. Additionally, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.

Hepatic impairment.

In volunteers with mild to moderate hepatic cirrhosis (Child–Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers without hepatic impairment. Pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been reported.

Clinical characteristics.

Indications.

Treatment of men with erectile dysfunction, manifested as the inability to achieve or maintain an erection of the penis sufficient for successful sexual intercourse.

For Filapu to be effective, sexual stimulation is required.

Contraindications.

• Hypersensitivity to sildenafil or to any of the excipients of the medicinal product.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathway and potentiates the hypotensive effect of nitrates.
• Medicinal products for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g., patients with severe cardiovascular disorders such as unstable angina or severe heart failure).
• Concomitant use of phosphodiesterase-5 (PDE5) inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Sildenafil citrate is contraindicated in patients who have lost vision in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether such episodes were associated with prior use of PDE5 inhibitors.
• The safety of sildenafil has not been studied in the following patient subgroups, and therefore its use is contraindicated: severe hepatic impairment, arterial hypotension (blood pressure < 90/50 mm Hg), recent myocardial infarction, and known hereditary retinal degenerative disorders such as retinitis pigmentosa (a smaller proportion of such patients have a genetic defect in retinal phosphodiesterase).

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil.

In vitro studies.
Sildenafil metabolism is primarily mediated by cytochrome P450 (CYP) isoenzymes 3A4 (major pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.

In vivo studies.
Population pharmacokinetic analysis of clinical trial data showed reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse events was not observed in such patients, an initial dose of 25 mg is recommended when sildenafil is co-administered with CYP3A4 inhibitors.

Concomitant administration of the potent HIV protease inhibitor ritonavir, a strong inhibitor of P450, at steady state (500 mg twice daily) with sildenafil (single dose – 00 mg) resulted in a 300% increase (4-fold) in sildenafil maximum concentration (Cmax) and a 1000% increase (11-fold) in sildenafil plasma area under the concentration-time curve (AUC). At 24 hours, plasma sildenafil concentration remained approximately 200 ng/mL compared to 5 ng/mL with sildenafil alone. This is consistent with the pronounced effect of ritonavir on a wide range of P450 substrates. Sildenafil did not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic findings, concomitant administration of sildenafil with ritonavir is not recommended, and under no circumstances should the maximum sildenafil dose exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times daily) with sildenafil (single dose 100 mg) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil did not affect the pharmacokinetics of saquinavir.

It can be expected that other potent CYP3A4 inhibitors such as ketoconazole and itraconazole will have a more pronounced effect. A single 100 mg dose of sildenafil co-administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure to sildenafil (AUC). In healthy male volunteers, no effect was observed of azithromycin (500 mg once daily for 3 days) on AUC, Cmax, Tmax, elimination rate constant, or corresponding elimination half-life of sildenafil or its major circulating metabolites. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, when co-administered with sildenafil (50 mg) in healthy volunteers, increased plasma sildenafil concentration by 56%.

Grapefruit juice is a weak inhibitor of intestinal wall CYP3A4 metabolism and may moderately increase sildenafil plasma levels.

A single dose of antacid (magnesium hydroxide/aluminum hydroxide) did not affect sildenafil bioavailability.

Although there are no reports of specific interaction studies with other medicinal products, population pharmacokinetic analysis showed that concomitant administration of drugs belonging to the following classes does not affect sildenafil pharmacokinetics: CYP2C9 inhibitors (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants), thiazide and related diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, beta-blockers, or CYP450 metabolism inducers (rifampicin, barbiturates).

Nicorandil is a hybrid potassium channel activator and nitrate. Due to its nitrate component, it can cause a serious interaction with sildenafil.

Effect of sildenafil on other medicinal products.

In vitro studies.
Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Considering that the maximum plasma concentration of sildenafil after the recommended dose is approximately 1 µmol, it is unlikely that sildenafil will affect the clearance of substrates of these isoenzymes.

There is no available information regarding interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies.
Due to the known effect of the drug on the nitric oxide/cGMP metabolic pathway, sildenafil has been shown to potentiate the hypotensive effect of nitrates; therefore, concomitant use with nitric oxide donors or nitrates in any form is contraindicated.

Concomitant administration of sildenafil to patients taking alpha-blockers may, in some sensitive individuals, lead to the development of arterial hypotension with clinical manifestations. The likelihood of this is highest within 4 hours after sildenafil intake. According to published data from three specific drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were co-administered to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In this population, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean additional reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4.5 mm Hg, respectively. Rare reports have been received of postural hypotension with clinical manifestations in patients stabilized on doxazosin therapy who received sildenafil concomitantly. These reports described dizziness and mild impairment of consciousness, but not loss of consciousness.

Sildenafil citrate enhances the hypotensive effect when used concomitantly with medicinal products containing sacubitril/valsartan.

No significant interaction was observed with concomitant administration of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), drugs whose metabolism involves CYP2C9.

Sildenafil (50 mg) did not enhance the bleeding time prolongation caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not enhance the hypotensive effect of alcohol in healthy volunteers with a mean maximum blood alcohol level of 80 mg/dL.

A combined analysis of data on classes of antihypertensive agents, such as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenergic blockers, revealed no differences in the adverse effect profile in patients taking sildenafil compared to placebo treatment. According to published results of specific interaction studies, concomitant administration of sildenafil (100 mg) with amlodipine in patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure. The corresponding additional reduction in supine diastolic blood pressure was 7 mm Hg. This additional blood pressure reduction was similar in magnitude to that observed with sildenafil alone in healthy volunteers.

Sildenafil (100 mg) did not affect the steady-state pharmacokinetics of HIV protease inhibitors saquinavir and ritonavir, which are CYP3A4 substrates.

Riociguat. Study data demonstrated an additive systemic effect on blood pressure reduction when PDE5 inhibitors were used concomitantly with riociguat. In patients participating in the studies, no positive clinical effect was observed from the concomitant use of PDE5 inhibitors with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Special precautions for use.

Before considering pharmacological treatment, a medical history should be taken and a physical examination performed to establish the diagnosis of erectile dysfunction and to determine its underlying possible causes.

Before initiating any treatment for erectile dysfunction, the physician should assess the patient's cardiovascular status and the degree of cardiac risk associated with sexual activity. Sildenafil has vasodilatory properties that may cause mild and transient reduction in blood pressure. Before prescribing sildenafil, the physician must carefully consider whether the patient’s underlying medical conditions could lead to adverse consequences from such vasodilatory effects, particularly when the drug is used in combination with sexual activity. The drug should be prescribed with caution in patients who are particularly sensitive to vasodilators, including those with conditions associated with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or in patients with the rare multisystem disorder known as systemic atrophy, which manifests as marked impairment of autonomic blood pressure regulation.

Sildenafil citrate potentiates the hypotensive effect of nitrates.

During post-marketing surveillance, reports have been received of serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which were temporally associated with the use of sildenafil citrate. Most (but not all) of these patients had underlying cardiovascular risk factors. A significant number of events occurred during or immediately after sexual activity; in several reports, events occurred shortly after taking sildenafil citrate even in the absence of sexual activity. It is not possible to determine whether these events are directly related to the aforementioned factors or have other causes.

Sildenafil citrate enhances the hypotensive effect when used concomitantly with medicinal products containing sacubitril/valsartan.

Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernous fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

The safety and efficacy of combining sildenafil with other treatments for erectile dysfunction have not been reported. Therefore, such combinations are not recommended.

Spontaneous reports of visual disturbances and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been received in connection with the use of sildenafil and other PDE5 inhibitors. Patients should be advised to discontinue sildenafil citrate immediately and seek medical advice if they experience sudden visual loss or visual disturbances.

Concomitant use of sildenafil and ritonavir is not recommended.

Sildenafil should be used with caution in patients taking alpha-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some predisposed individuals. Symptomatic hypotension usually occurs within 4 hours after taking sildenafil. To minimize the risk of orthostatic hypotension, sildenafil therapy should only be initiated in patients who are hemodynamically stable on alpha-blocker therapy. The recommended initial dose for such patients is 25 mg of sildenafil. In addition, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Platelet studies in humans have shown that sildenafil enhances the anti-aggregatory effect of sodium nitroprusside in vitro. There is no safety data available on the use of sildenafil in patients with bleeding disorders or active peptic ulcers. Therefore, sildenafil should be administered to these patients only with caution.

Hearing loss. Physicians should advise patients to stop taking PDE5 inhibitors, including sildenafil, and seek immediate medical attention if they experience sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitors, including sildenafil-containing products. It is not possible to determine whether these events are related to the use of PDE5 inhibitors or to other factors.

Concomitant use with antihypertensive agents. Sildenafil exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a separate drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted diseases. The use of sildenafil does not protect against sexually transmitted diseases. Consideration should be given to advising patients about appropriate preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus (HIV).

Fertility. No effects on sperm morphology or motility were observed in healthy volunteers after administration of a 100 mg dose.

The medicinal product contains the azo dye Ponceau 4R (E 124), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Sildenafil citrate is not indicated for use in women.

Effect on ability to drive or operate machinery.

The medicinal product may have a minor influence on the ability to drive or operate machinery.

Since visual disturbances were observed during clinical trials, patients should determine their individual response to sildenafil citrate before driving or operating machinery.

Method of Administration and Dosage

Filap tablets are intended for oral administration.

Use in Adults

The recommended dose is 50 mg, taken as needed approximately 1 hour before sexual intercourse. Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg*. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. If sildenafil citrate is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Use in Elderly Men

Dose adjustment is not required in elderly men.

Use in Patients with Renal Impairment

In patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), the dosage regimen does not need to be changed.

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), a starting dose of 25 mg* is recommended. Based on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Use in Patients with Hepatic Impairment

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), a starting dose of 25 mg* is recommended. Based on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Use in Children and Adolescents

Sildenafil citrate is not indicated for use in individuals under 18 years of age.

Use in Patients Taking Other Medications

Except for ritonavir, whose concomitant use with sildenafil is not recommended, treatment of patients receiving concomitant therapy with CYP3A4 inhibitors should be initiated at a dose of 25 mg*.

To minimize the risk of postural hypotension, patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. Additionally, sildenafil therapy should be initiated at a dose of 25 mg*.

* Administer the medicinal product at the appropriate dosage strength.

Children

The product is not indicated for use in individuals under 18 years of age.

Overdose

In clinical studies involving healthy volunteers receiving single doses up to 800 mg, adverse reactions were similar to those observed at lower doses, but their frequency and severity increased. Administration of 200 mg did not result in increased efficacy, while the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances) increased.

In cases of overdose, symptomatic treatment should be administered if necessary. Since sildenafil is highly protein-bound and not significantly excreted in urine, hemodialysis is not expected to accelerate drug clearance.

Adverse Reactions

The most commonly reported adverse reactions were headache, flushing, visual disturbances, cyanopsia, blurred vision, colour vision disturbances, dyspepsia, nasal congestion, dizziness, back pain, nausea, and hot flushes.

All clinically significant adverse reactions observed in clinical studies more frequently than with placebo are listed below by System Organ Class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Additionally, the frequency of clinically significant adverse reactions reported during post-marketing experience is categorized as unknown.

Immune system disorders:
Rare: hypersensitivity reactions.

Nervous system disorders:
Very common: headache;
Common: dizziness;
Uncommon: somnolence, hypoesthesia;
Rare: stroke, loss of consciousness, transient ischaemic attack, seizures, seizure recurrence.

Eye disorders:
Common: visual disturbances, blurred vision, colour vision disturbances;
Uncommon: conjunctival disorders, lacrimation disorders, eye pain, photophobia, photopsia, eye hyperaemia, visual brightness, conjunctivitis.
Rare: non-arteritic anterior ischaemic optic neuropathy, retinal vessel occlusion, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights, eye oedema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, ocular discomfort, eyelid oedema, scleral discolouration.

Ear and labyrinth disorders:
Uncommon: vertigo, tinnitus;
Rare: deafness (several cases of sudden hearing decrease or sudden hearing loss have been reported with PDE5 inhibitors, including sildenafil).

Vascular disorders:
Common: facial flushing, hot flushes;
Uncommon: hypertension, hypotension.

Cardiac disorders:
Uncommon: palpitations, tachycardia;
Rare: myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, sudden cardiac death.

Respiratory, thoracic and mediastinal disorders:
Common: nasal congestion;
Uncommon: epistaxis, nasal sinus congestion;
Rare: throat tightness, nasal mucosal oedema, nasal dryness.

Gastrointestinal disorders:
Common: nausea, dyspepsia;
Uncommon: vomiting, dry mouth, gastroesophageal reflux disease, upper abdominal pain;
Rare: oral hypoesthesia.

Skin and subcutaneous tissue disorders:
Uncommon: skin rash;
Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:
Uncommon: myalgia, limb pain.

Reproductive system and breast disorders:
Rare: priapism, prolonged erection, penile haemorrhage, haemospermia.

Renal and urinary disorders:
Uncommon: haematuria.

Infections and infestations:
Uncommon: rhinitis.

General disorders:
Uncommon: chest pain, increased fatigue, feeling of warmth;
Rare: irritation.

Investigations:
Uncommon: increased heart rate.

The following events were observed in < 2% of patients during controlled clinical trials; a causal relationship has not been established. Reports included events with a probable association with the use of the medicinal product. Events not listed were mild and reports were too imprecise to be meaningful.

General: facial oedema, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischaemia, cerebral vessel thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal tract: glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, abnormal liver function tests, rectal haemorrhage, gingivitis.

Blood and lymphatic system disorders: anaemia, leukopenia.

Metabolism and nutrition disorders: thirst, oedema, gout, unstable diabetes, hyperglycaemia, peripheral oedema, hyperuricaemia, hypoglycaemia, hypernatraemia.

Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous system: ataxia, neuralgia, neuropathy, paraesthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory system: asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin: urticaria, herpes, pruritus, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes.

Urinary and reproductive system: cystitis, nocturia, increased frequency of urination, gynaecomastia, urinary incontinence, ejaculation disorder, genital swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified after the product was marketed. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are reported due to their severity, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular, cerebrovascular and vascular disorders: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebrovascular haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with sildenafil use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after sildenafil use without sexual activity. Other events occurred within several hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are directly related to the use of the drug, to sexual activity, to underlying risk factors, to a combination of these factors, or to other factors.

Blood and lymphatic system disorders:
Vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial hypertension secondary to sickle cell anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this finding for patients using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system disorders:
Anxiety, transient global amnesia.

Specific sensations.

Hearing. After marketing, cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported. In some cases, medical conditions and other factors that may have contributed to hearing-related adverse events were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to sildenafil use, to underlying risk factors for hearing loss, to a combination of these factors, or to other factors.

Vision. Transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

Rarely, after marketing, cases of non-arteritic anterior ischaemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including sildenafil. Many, but not all, patients had underlying anatomical or vascular risk factors for NAION, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidaemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, to underlying anatomical or vascular risk factors, to a combination of these factors, or to other factors.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national reporting requirements.

Shelf life. 2 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.
50 mg: 1 or 4 film-coated tablets in a blister pack, 1 blister per cardboard box;
100 mg: 1 film-coated tablet in a blister pack, 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer.
Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.
V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.